Thiolactomycin (TLM) is a natural product thiolactone first isolated from Nocardia sp., a bacterial strain identified from a Japanese soil sample in 1981 (4). TLM is rapidly absorbed in rats when administered both orally and by intramuscular injection, and it provides protection from both urinary tract and oral infections in animals infected with Serratia marcescens and Klebsiella pneumoniae (14).
The antibacterial activity of TLM is known to result from an inhibition of fatty acid biosynthesis. TLM is a selective and reversible inhibitor of the KAS enzymes in the FAS-II pathway (4, 6, 16), but does not inhibit the mammalian FAS-I enzymes (17). TLM resistant E. coli strains contain mutations in the fabB KAS gene (18) and overproduction of FabB confers TLM resistance in vivo (19) suggesting that FabB is the major cellular target. Based on kinetic and structural data, TLM is thought to be a competitive inhibitor of malonyl-ACP (5-6), and studies have shown that TLM binds preferentially to the covalently modified KAS acyl-enzyme intermediate with slow onset kinetics (15).
Although slow onset kinetics are observed when TLM binds to acyl-KasA (15), the inhibitor only has a Ki* value of 2 μM for the C171Q acyl-enzyme mimic (7, 15). The properties of TLM have stimulated efforts aimed at making analogs with improved antibacterial activity of the compound. These studies have primarily concentrated on the 5 position of the TLM ring primarily due to ease of synthesis (20-24). However, these studies have failed to improve the activity of TLM. Described herein, is a new class of TLM analogue antibiotics.